1-155066845-A-G

Variant names:

• chr1-155066845-A-G
• rs138277393
• NM_005227.3:c.229A>G
• EFNA4 p.Met77Val

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PVS1_ModerateBS2

The NM_001406810.1(EFNA4):c.1A>G (p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. Note: NM_001406810.1 is not a MANE Select or MANE Plus Clinical transcript for EFNA4; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant disrupts the start codon, preventing normal translation initiation. The variant allele was found at a cumulative frequency of 0.0000291 (AC=47) in the gnomAD database across 1,613,898 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00032. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: EFNA4 NM_001406810.1 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.08
• Publications: 0 publications found

Genes affected

EFNA4 (HGNC:3224): (ephrin A4) This gene encodes a member of the ephrin (EPH) family. The ephrins and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases and have been implicated in mediating developmental events, especially in the nervous system and in erythropoiesis. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. This gene encodes an EFNA class ephrin that has been implicated in proliferation and metastasis of several types of cancers. [provided by RefSeq, May 2022]

EFNA4 Gene-Disease associations (from GenCC):

• craniosynostosis

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

EFNA4-EFNA3 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Start-lost with downstream start: >10% CDS truncated — moderate (PVS1 downgraded to PM); Start codon lost (exon 3 of 5); downstream rescue start codon present, but it truncates more than 10% of the CDS.
	BS2Observed in healthy adult		Pure AD gene with cumulative gnomAD AC ≥5 — observed in healthy adults (BS2); GnomAD homozygous count = 0.; Cumulative gnomAD AC = 47 (pure AD gene, not AR).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001406810.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	EFNA4 NM_005227.3	MANE Select	c.229A>G p.Met77Val	missense	Exon 2 of 4	Prot: NP_005218.1 UniProt:
	EFNA4 NM_001406810.1		c.1A>G p.Met1?	start_lost	Exon 3 of 5	Prot: NP_001393739.1
	EFNA4 NM_182689.2		c.229A>G p.Met77Val	missense	Exon 2 of 4	Prot: NP_872631.1 UniProt:

EFNA4 NM_005227.3

MANE Select

HGVSc / HGVSpc.229A>Gp.Met77Val

Exon rankExon 2 of 4

missense

Prot: NP_005218.1UniProt: P52798-1

EFNA4 NM_001406810.1

HGVSc / HGVSpc.1A>Gp.Met1?

Exon rankExon 3 of 5

start_lost

Prot: NP_001393739.1

EFNA4 NM_182689.2

HGVSc / HGVSpc.229A>Gp.Met77Val

Exon rankExon 2 of 4

missense

Prot: NP_872631.1UniProt: P52798-3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	EFNA4 ENST00000368409.8	TSL:1MANE Select	c.229A>G p.Met77Val	missense	Exon 2 of 4	Prot: ENSP00000357394.3 UniProt:
	EFNA4 ENST00000359751.8	TSL:1	c.229A>G p.Met77Val	missense	Exon 2 of 4	Prot: ENSP00000352789.4 UniProt:
	EFNA4-EFNA3 ENST00000505139.1	TSL:2	c.113+2909A>G	intron	Intron 1 of 4	Prot: ENSP00000426741.1 UniProt:

EFNA4 ENST00000368409.8

TSL:1MANE Select

HGVSc / HGVSpc.229A>Gp.Met77Val

Exon rankExon 2 of 4

missense

Prot: ENSP00000357394.3UniProt: P52798-1

EFNA4 ENST00000359751.8

TSL:1

HGVSc / HGVSpc.229A>Gp.Met77Val

Exon rankExon 2 of 4

missense

Prot: ENSP00000352789.4UniProt: P52798-2

EFNA4-EFNA3 ENST00000505139.1

TSL:2

HGVSc / HGVSpc.113+2909A>G

Exon rankIntron 1 of 4

intron

Prot: ENSP00000426741.1UniProt: K9J7H7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000138	AC:21	Hom:0	AN:152192	Cov:32
GnomAD2 exomes	AF: 0.0000757	AC:19	Hom:	AN:250970	Cov:
GnomAD4 exome	AF: 0.0000178	AC:26	Hom:0	AN:1461706	Cov:32
GnomAD4 genome	AF: 0.000138	AC:21	Hom:0	AN:152192	Cov:32
TOPMed (Bravo)	AF: 0.000117	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000111	AC:4	Hom:0	AN:36010	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13006	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41958	0.0000299	2	66888
SCHEMA(Schizophrenia)	0.0000884	10	113084	0.0000578	11	190474

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	0.047
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.97	D
FuncVEP CTI	Benign	0.010
GPN-Star LLR	N/A	-4.3
GPN-Star score	N/A	4.3
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	0.34	D
Mutation Taster	N/A	90/10	polymorphism
MutationAssessor	Uncertain	2.5	M
PhyloP100	Uncertain	4.1
popEVE	Benign	-3.6
PROVEAN	Uncertain	-3.4	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Uncertain	0.53
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.045	D
Varity_R	N/A	0.27
VESM-3B	Benign	-8.0

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.040
SpliceAI score (max)	Benign	0.080	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs138277393;

hg19: chr1-155039321;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar